In-Cell Dynamics: The Next Focus of All-Atom Simulations

Abstract

The cell is a crowded space where large biomolecules and metabolites are in continuous motion. Great strides have been made in in vitro studies of protein dynamics, folding, and protein-protein interactions, and much new data are emerging of how they differ in the cell. In this Perspective, we highlight the current progress in atomistic modeling of in-cell environments, both bacteria and mammals, with emphasis on classical all-atom molecular dynamics simulations. These simulations have been recently used to capture and characterize functional and non-functional protein-protein interactions, protein folding dynamics of small proteins with varied topologies, and dynamics of metabolites. We further discuss the challenges and efforts for updating modern force fields critical to the progress of cellular environment simulations. We also briefly summarize developments in relevant state-of-the-art experimental techniques. As computational and experimental methodologies continue to progress and produce more directly comparable data, we are poised to capture the complex atomistic picture of the cell.

Figure 1.

All-atom in-cell modeling captures (a) protein-protein interactions., (b) protein folding dynamics (adopted from with persmission from ref.), and (c) metabolite dynamics (adopted with permission from ref.). Background: human U-2 OS cell (image is courtesy of Dr. Y. A. Golubeva). Copyright 2023 American Chemical Society.

Figure 2.

All-atom in cell model assembly: (a) initial packing of macromolecules followed by rigid-body Brownian dynamics with Atomic Resolution Brownian Dynamics (ARBD), (b) pack metabolites and ions, and (c) add explicit water molecules.

Figure 3.

Transient protein-protein interactions in cell: (a) distribution of protein–protein contact sizes for C22*, C36m, and C36mCU models, (b) distribution of protein–protein contact lifetimes (c) metabolon: PGK (blue), GAPDH (green), and PGM (orange) (ref.). (a) and (b) reproduced with permission from ref. Copyright 2019 American Chemical Society.

Figure 4.

Protein folding dynamics in cell: (a) native β-hairpin is formed in GTT protein (orange) surrounded by other macromolecules (blue) and numerous metabolites and ions (white), (b) water expulsion during formation of a native GTT β-hairpin, (c) initiation of aggregation by two copies of unfolded PB (magenta and green) (ref.). (a) and (b) reproduced with permission from ref. Copyright 2020 American Chemical Society.